Genitourinary Issues During Spaceflight: a Review

International Journal of Impotence Research (2005) 17, S64–S67 & 2005 Nature Publishing Group All rights reserved 0955-9930/05 $30.00 www.nature.com/ijir Genitourinary issues during spaceflight: a review

JA Jones1*, R Jennings2, R Pietryzk3, N Ciftcioglu4 and P Stepaniak1

1NASA/Johnson Space Center, Houston, Texas, USA; 2University of Texas Medical Branch, Galveston, Texas, USA; 3M.S. Enterprise Advisory Services, Inc., Houston, Texas, USA; and 4Nanobac Life Sciences, Inc., Tampa, Florida, USA

The genitourinary (GU) system is not uncommonly affected during previous spaceflights. GU issues that have been observed during spaceflight include urinary calculi, infections, retention, waste management, and reproductive. In-flight countermeasures for each of these issues are being developed to reduce the likelihood of adverse sequelae, due to GU issues during exploration-class spaceflight, to begin in 2018 with flights back to the Moon and on to Mars, according to the February 2004 Presendent’s Vision for US Space Exploration. With implementation of a robust counter- measures program, GU issues should not have a significant threat for mission impact during future spaceflights. International Journal of Impotence Research (2005) 17, S64–S67. doi:10.1038/sj.ijir.3901431

Keywords: spaceflight; genitourinary; reproduction; calculi, urinary retention

Introduction Urinary calculi have been observed on one occasion in-flight and 14 occasions postflight. The one in-flight episode occurred in a Russian cosmo- There are many physiological effects and medical naut during a long-duration mission on the Salyut, issues that impact spaceflight missions. The genito- which nearly resulted in the crewmember being urinary (GU) system is not uncommonly affected medically evacuated due to inability to control his during spaceflight. In total, 10% of astronauts pain resulting from transient obstruction of the participating in Shuttle flights between 1981 and upper collecting system from a stone lodged in the 1998 (89 missions), which included 508 crew (439 distal ureter. In total, 11 US crewmembers have had men, 69 woman) over 4443 flight days, reported GU 14 urinary calculi following their spaceflights, all symptoms during flight. after missions less than 2 weeks in duration.1,2 Obviously, issues in the GU system can adversely Space travelers are at risk of urinary calculi due to affect the sexual health of the astronaut and there- the mobilization of calcium from the bone when fore have relevance to the focus of this special issue. exposed to prolonged microgravity. Due to tight regulation of calcium levels in the blood, the mobilized bone mineral during periods of un- weighting is excreted by the kidney, resulting in Issues of GU health increased concentration of calcium in the urine, and thereby increased solubility product of calcium salts GU issues during spaceflight can be categorized as like calcium oxalate. Long-duration spaceflight in follows: upper tract, lower tract, waste management, LEO (Low Earth Orbit) poses a greater risk for an and reproductive health. in-flight stone. Exploration Missions envisioned for the Moon and Mars will vary in mission length from a few weeks to perhaps 2–3 y. During these missions, the Upper tract transit phase from LEO to the planetary surface, traversing interplanetary space, will likely expose the crewmember to microgravity for extended The two previously observed conditions affecting periods, ranging from 4 to 6 days between the Earth the upper tracts during spaceflight are calculi and and Moon to 4–9 months, depending on the related obstruction. propulsion system and vehicle trajectory. After reaching the planetary surface, the crewmember’s musculoskeletal system will be under the influence *Correspondence: JA Jones, MD, NASA/Johnson Space of reduced or partial gravity. In the case of the Moon, Center, Houston, TX, USA. the gravity is approximately 1/6 of that of the Earth, Genitourinary issues during spaceflight JA Jones et al S65 while on Mars approximately 1/3 (0.38 g). It is not Diagnosis of UTI is aided on-orbit by urine chem- currently known how well ambulation in partial istry analysis strips (US) and an onboard urine gravity will maintain the musculoskeletal system analyzer (Russian). The combination of symptoms on its own; hence, the need for both transit phase plus positive findings of leukocyte esterase or and planetary surface operational countermeasures. nitrites on the urine strip make a diagnosis of UTI Also for Mars missions, a contingency management very likely. UTIs are easily treated with oral strategy has been developed at NASA/JSC for antibiotics flown in the ambulatory medical kit. endoscopic management of a ureteral calculus Countermeasures for UTIs include good perineal during spaceflight under ultrasound guidance.3 hygiene, clean urine collection system interface, A question currently under investigation at the adequate fluid hydration, and nominal time to void NASA/JSC by N Ciftcioglu and co-workers is after urge to void sensed (minimal delay in voiding). whether nanobacteria, which may have been found Occasionally, if the GU system is compromised by an in 1996 inside a Martian meteorite, can play a role in indwelling catheter or intermittent catheterization the pathogenesis of human calcific diseases such (ICC-Intermittent Clean Catheterization), then pro- as urinary and prostatic calculi. Nanobacteria or phylactic antisepsis or antibiotics can be used, for ‘nanoparticles’ have been found to reproduce more example, qHS nitrofurantoin while receiving ICC.8 vigorously in bioreactor microgravity simulators, and thus may pose a greater hazard in microgravity than on the ground, if their human pathogenecity is Retention. In the history of short-duration flight proven.4,5 on the Space Shuttle, there have been four cases of urinary retention requiring bladder catheterization. Another potential countermeasure, which that has The cause of these cases is again multifactorial, and been evaluated in ambulatory bedrest subjects, and extensively in clinical use for osteoporosis patients includes pharmacologic side effects (anticholiner- 6 gics such as antiemetics used to treat space motion is the bisphosphonate Aledronate. Bisphospho- sickness), delay in voiding (due to schedule and nates act by inhibiting the action of osteoclasts in mobilizing calcium from bone hydroxyapatite. waste control system availability), impaired sensor- ium, and possibly even microgravity itself (psycho- Bisphosphonates, like AG, have the potential to be logical and lack of gravity vector differences in protective of both the musculoskeletal and GU 9 systems by reducing the loss of bone mineral voiding technique). The added risks associated calcium. An ISS spaceflight study of the bispho- with long-duration flight for urinary retention are two-fold: (1) possibility of outlet obstruction from sphonates Aledronate and Zoledronic acid was recently approved by nonadvocate review team prostate or urethral infection/inflammation, and (2) reporting to NASA headquarters (Supplemental progression or recurrence of a pre-existing condi- tion, for example, a urethral stricture managed by Medical Objective Leblanc, JA Jones et al). It is dilatation, may have time to recur during a long- expected that bisphosphonates will be used syner- gistically with resistive exercise and perhaps AG if it duration flight. Screening should be performed for preflight conditions with potential for recurrence/ is operationally employed for exploration missions. progression and most likely excluded from long The last countermeasure that may be effective for reducing the risk of urinary calculi in flight is duration flight eligibility. currently under flight study on the Shuttle and ISS, Countermeasures for urinary retention include avoiding delays in voiding, selection criteria for is potassium citrate, in the form of Urocit-Kt (Mission Pharmacal).7 A mid-study interim analysis predisposing conditions as mentioned above, plus is being conducted by the investigators at the time of close monitoring of crew receiving anticholinergic medications, to include ICC if required to drain this manuscript preparation. urine from bladder before overdistension injury can occur. Lower tract

Urinary waste Urinary tract infections (UTIs). UTIs have oc- curred on multiple occasions during spaceflight with multiple likely causative mechanisms. Cer- Urine is disposed of on-orbit via waste collection tainly, individual physical and mental stress, dehy- systems (WCS). Both the US and Russian toilets take dration and hygiene likely played a role during the advantage of negative pressure induced from fluid UTI acquired during Apollo 13. Other hygiene separation systems to effectively ‘acquire’ liquid issues such as collection devices and factors such waste from the crewmember (mild suction like a as delayed access to voiding and urinary stasis are weak shop vacuum cleaner). In both systems, a thought to also play a role in the UTI cases. One case funnel attached to a length of flexible tubing serves of prostatitis on the Salyut resulted in sepsis and as the point of interface between the WCS and the subsequently a medical evacuation of the patient. crewmember.

International Journal of Impotence Research Genitourinary issues during spaceflight JA Jones et al S66 Reproductive health

The known postflight effects of short duration (mean 9 day spaceflights) in LEO on all US astronauts, male and female, are as follows:  Have had normal conception in both genders within 1 week after space flight,  56 post-flight pregnancies,  11 pregnancies within 1 y of space mission,  17 postflight births in female astronauts,  9 miscarriages; 2 stillbirths in all astronaut couples (4/11 in female astronauts),  2 with chronic genetic diseases,  43 healthy children. Figure 1 % of successful pregnancies vs age in women using own vs donor eggs. These data are summarized with the knowledge that not all potential conception events and sponta- neous abortions are captured. This rate of loss Based on the analysis of the current astronaut compares reasonably to the US miscarriage rate over pool, about 80% come to NASA without previously the last several decades of: 10–20%—women age having delivered children. The average maternal age 20s, 25%—age 30s, 33%—age 40, 50%—445. in successful pregnancies occurring after spaceflight Considering the usual delay in pregnancy and is 41–42 y. By this time, the chance for genetic average age of conception and delivery in the US defects and miscarriage has increased considerably, female astronaut corps, it does not appear that short- as stated above, and fertility has declined. In fact, duration spaceflight has an adverse affect on the many astronauts have been unsuccessful in con- ability of astronauts to conceive and bear healthy ceiving at this stage of their life even though they children to term. However, age, due to the chosen have used all the technology available. In addition, delay in conception resulting in increased age, and the known miscarriage rate in female astronauts perhaps other factors, for example occupational after spaceflight exceeds 40%. While this high rate stress, there may be an issue with fertility in female is most likely due to age, it reduces the chance of crewmembers. successfully completing a pregnancy. Figure 1 is compiled from SART data and was provided by Dr Bill Gibbons from the Jones Institute at the Eastern Assisted reproductive technology Virginia Medical School. This was the first institu- tion in the US to perform successful IVF. It clearly shows the reduction in successful pregnancies with There are several factors that support the need for a IVF based on age, with the decrease beginning at policy at NASA regarding Assisted Reproduction 32 y of age (exact average age of a new astronaut). Technology (ART) for astronauts. The primary Spontaneous pregnancies undergo a similar age- concerns are age-related fertility decline that occurs based decrease. We do not know if spaceflight per se as female astronauts delay pregnancies for training/ affects fertility (Figure 1). spaceflight and the effect of radiation-induced The effects of long-duration flight and especially gamete damage for individuals of both sexes. The exploration class spaceflight on the reproductive per-cycle fecundability for natural and assisted capacity of humans are not currently known. cycles begins to decrease considerably in women Since the radiation environment found on Earth at age 32. This is not a particular problem for men. does not contain the highly ionized heavy particles Since the average age of an incoming female found in space that penetrate tissue deeply and may astronaut is 32, and many wish to delay pregnancy cause important nuclear damage, it is difficult to until after their first spaceflight, most are approach- provide guidance regarding risks to male or female ing 40 by the time an appropriate window opens for gametes in spaceflight. On-going studies at the them to conceive. Pregnant astronauts are not Brookhaven National Laboratories accelerator may allowed to train in the NBL, vacuum chamber, KC- help reduce the risk uncertainty. One solution to 135 zero G aircraft, or fly in T-38s during their this problem is to provide a program for individuals pregnancies. Pregnancy is prohibited for spaceflight. of both sexes to store gametes on Earth for future Some international travel is also restricted. In order use. This is especially true for planned exploratory to complete necessary training and compete for missions to Mars missions, where there is still flight assignment with their selection classes, they sizeable uncertainty about the biological effects of female astronauts often usually avoid pregnancy high-energy particle radiation (HZE) on the repro- early in their astronaut careers. ductive tissues. For women, banking eliminates the

International Journal of Impotence Research Genitourinary issues during spaceflight JA Jones et al S67 potential problem of damage to gametes due to actual historical pre-, in- and postflight medical galactic cosmic radiation, solar particle events, and events, as well as assessment of what future flight trapped radiation. It also augments fertility since the challenges lay ahead. However, a well-designed pregnancy and miscarriage rates for embryo transfer strategy of selection, monitoring, and preventive are dependent on the age of the gametes at the time medicine with effective countermeasures, along of collection. Cryopreservation of embryos is pre- with an easily implementable program of early ferred because the technology to store oocytes is not imaging diagnosis and minimally invasive contin- yet reliable. Eventually, other options may include gency intervention, should prevent GU issues from the cryopreservation of ovarian tissue. For male having any significant mission impact for solar crewmembers, sperm cryopreservation technology system exploration. is well established and easily implemented with long-duration storage capability. There is no currently NASA-sponsored program for assisted reproductive technology for astronauts Acknowledgements of either gender. The female astronauts who have used ART for fertility reasons (approximately 10 individuals or about 25% of all women astronauts) Dr Larry Lipshultz, Department of Urology, Baylor have done so at their own expense. NASA is College of Medicine, Adrian Leblanc at USRA and considering the budgetary impact of supporting Shannon Melton at Wyle Laboratories. ART services for its crewmembers. The delay in obtaining pregnancies while younger is due in large part to the unpredictable flight schedule and sacrifices made for the program during training. References Other than the problem with radiation exposure to gametes, this situation is unique for the female astronauts because the male astronaut’s ability to 1 Pietrzyk RA, Jones JA, Sams CF, Whitson PA. Characteristics of renal stone formation among US astronauts. Aviation Space have a family is not tied to the flight or training Environ Med 2005 (submitted). schedule. 2 Pietryzk R, Whitson P, Jones J, Sams C. Overview of renal stones In-flight reproductive activity is possible from and space flight. Bulletin of the 14th International Academy of studies on multiple species that have flown in space Astronautics—Humans in Space Symposium: Living in Space: Scientific, Medical, and Cultural Implications, Banff, Alberta, on several prior short duration flights, both in the Canada, May 22 2003. Russian (Bion) and US (Shuttle) programs. There 3 Jones JA, Johnston S, Campbell M, Billica R. Endoscopic have been both normal and abnormal reproduction surgery and telemedicine in microgravity, developing contin- patterns in animals observed during spaceflight. gency procedures for exploratory class space flight. Urology Animals studied include those pregnant prior to 1999; 53: 892–897. 4 Jones JA et al. Association of calcifying nanoparticles within launch and those pregnant immediately after serum and prostates of patients with prostatic inflammation launch. Several species were observed to have and hyperplasia: a preliminary analysis. Society of Inflamma- diminished mating rates and relatively higher tion and Infection in Urology Session at the American number of fetal deaths compared to terrestrial Urological Assn. Annual Meeting, San Antonio, TX 2005 May. 5 Kajander OE, Ciftcioglu N, Katya A, Garcia-Cuerpo E. Char- controls, but only in specific species, while other acteristics of nanobacteria and their possible role in stone species did not seem to be adversely affected during formation. Urol Res 2003; 31: 47–54. spaceflight. 6 Young LR. Artificial Gravity’ Encyclopedia of Space Science and Technology Vol 1. John Wiley and Sons, Inc.: New York, 2003 pp 138–151. 7 LeBlanc AD et al. Alendronate as an effective countermeasure Conclusions to disuse induced bone loss. J Musculoskel Neuron Interact 2002; 2: 335–343. 8 Pietrzyk RA et al. Renal stone risk during space flight GU medical events have shown to be an issue for assessment and countermeasure validation. USRA/DSLS Bio- investigator’s Workshop Abstract Volume. Annual Meeting. both short duration and long duration spaceflight, Galveston, TX, 2005 January 10–12. and are anticipated to also be a potential issue for 9 Jones JA, Whitson P. Genitourinary issues in space medicine. future exploration missions as well. This is based on In: Barratt M (ed). Clinical Space Medicine 2005 (in press).

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